Mitochondrial Ca²⁺ uptake is essential for synaptic plasticity in pain

The increase of cytosolic free Ca²⁺([Ca²⁺]_c) due to NMDA receptor activation is a key step for spinal cord synaptic plasticity by altering cellular signal transduction pathways. We focus on this plasticity as a cause of persistent pain. To provide a mechanism for these classic findings, we report that [Ca²⁺]_c does not trigger synaptic plasticity directly but must first enter into mitochondria. Interfering with mitochondrial Ca²⁺ uptake during a [Ca²⁺]_c increase blocks induction of behavioral hyperalgesia and accompanying downstream cell signaling, with reduction of spinal long-term potentiation (LTP). Furthermore, reducing the accompanying mitochondrial superoxide levels lessens hyperalgesia and LTP induction. These results indicate that [Ca²⁺]_c requires downstream mitochondrial Ca²⁺uptake with consequent production of reactive oxygen species (ROS) for synaptic plasticity underlying chronic pain. These results suggest modifying mitochondrial Ca²⁺ uptake and thus ROS as a type of chronic pain therapy that should also have broader biologic significance.